The work on behaviorally conditioned immunosuppression is the most convincing evidence so far of the central nervous system's influence on immune functions. The basic paradigm has been to pair an immunosuppressive drug, cyclophosphamide (i.e., the unconditioned stimulus-US) with saccharin-flavored drinking water (i.e., the conditioned stimulus-CS). After one pairing, reexposure to the CS alone is able to produce immunosuppression. Although behaiorally conditioned immunosuppression is highly reproducible phenomenon, the magnitudeof the conditioned response is modest and is not sufficient to answer fundamental questions about the conditioning process or the immunological mechanisms responsible for the effect. The current belief is that the conditioned response is small because the paradigm involves pairing a CS for immunosuppression coincidently with another US (i.e., an antigenic stimulus) for activation of the immune system. The proposed investigation is intended to overcome this methadological hurdle. We have chosen two models of autoimmunity (i.e., autoantibody induction in normal mice, and spontaneous autoimmune diseases) where there is an excellent prospect of increasing the magnitude of the conditioned responses. In our first conditioning paradigm with normal mice, lipopolysaccaride (LPS) will be the US and saccharin-flavored drinking water will the CS. LPS is a polyclonal B cell activator that induces transient anti-nucleic acid antibodies in normal mice. We will then examine whether reexposure to the CS alone can mimic the response to LPS. In this paradigm there are no mixed messages to the organism, because both the US and the CA should have the same effect of potentiating the autoantibody response. In our second model we will examine the effects of behaviorally conditioned immunosuppression on two strains of autoimmune mice (MRL/1pr and BXSB) that develop a disease similar to systemic lupus erythematosus in man. In these experiments, cyclophosphamide will be the US and saccharin-flavored water will be the CS. Both the CS and the US are directed at immunosuppression, a process that is useful in maintaining homeostasis in these mice. Both of these models offer the opportunity of learning new information about the regulatory process of autoantibodies and autoimmune diseases as well as gaining new information about their clinical relevance.